The efficacy of tuberculosis control hinges on understanding the pathogenesis of tuberculosis in high-prevalence populations. Because most tuberculosis in the United States is thought to result from reactivation of prior infection, control efforts emphasize chemoprophylaxis for asymptomatic tuberculous infection. We hypothesize that primary tuberculosis is much more common than has been previously assumed, and that specific host factors favor rapid progression of tuberculous infection to disease. If this hypothesis is correct, more emphasis should be given to active case-finding and environmental controls to reduce disease transmission. We will test this hypothesis by using DNA fingerprinting to evaluate patterns of tuberculosis transmission in the urban homeless. In addition, we propose to facilitate detection of tuberculosis outbreaks through PCR-based DNA fingerprinting. Our specific aims are: 1) To determine the contribution of primary tuberculosis to tuberculosis morbidity in the homeless. This will be achieved by DNA fingerprinting of M tuberculosis isolates from 250 consecutive homeless patients in central Los Angeles, compared to isolates from stably housed patients, matched for age, sex, race and ethnicity. 2.1) To identify sites where development of primary tuberculosis is common. This will be achieved by correlating detailed epidemiologic and clinical data on homeless tuberculosis patients with results of DNA fingerprinting. 2.2) To identify the host factors that contribute to development of primary tuberculosis. The relative importance of specific host factors in favoring development of primary tuberculosis will be determined by comparing the distribution of these factors in homeless patients with primary tuberculosis and homeless control patients without tuberculosis. 3) To evaluate the utility of mixed linker DNA fingerprinting to direct targeted interventions that reduce tuberculosis transmission. Mixed linker DNA fingerprinting, based on PCR amplification of mycobacterial DNA, will be adapted for use on clinical samples and early mycobacterial cultures, then prospectively applied to all M tuberculosis isolates from homeless tuberculosis patients in central Los Angeles. In combination with the information obtained in aim 2, this will allow rapid recognition of unsuspected tuberculosis outbreaks and allow interventions targeted at specific sites and patient populations to reduce disease transmission.